The present invention relates to the use of known agonists of the central cannabinoid receptor CB1 for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy and craniocerebral trauma.
xcex949-Tetrahydrocannabinol (xcex949-THC) and, to a small extent, also xcex948-THC are the biologically active constituents in extracts of the plant Cannabis sativa (marihuana, hashish) and are responsible for the effects on the human central nervous system (CNS). Potential historical and contemporary therapeutic uses of cannabis preparations include, inter alia, analgesia, emesis, anorexia, glaucoma and motor disorders.
Up to now, two subtypes of cannabinoid receptors and a splice variant have been identified. The CB1 receptor (Nature 1990, 346, 561) and a splice variant CB1a (J. Biol. Chem. 1995, 270, 3726) are mainly localized in the central nervous system. The CB2 receptor was mainly found in the peripheral tissue, in particular in leucocytes, spleen and macrophages (Eur. J. Biochem. 1995, 232, 54).
CB1 and CB2 receptors have seven transmembrane regions and belong to the family of G protein receptors. Both receptors are negatively coupled via Gi/Go protein to adenylate cyclase and possibly negatively coupled to the presynaptic release of glutamate [cf. J. Neurosci. 1996, 16, 4322]. CB1 receptors are moreover positively coupled to potassium channels and negatively coupled to N- and Q-type calcium channels.
It is moreover known that the cannabinoid CB1 receptor agonists are subdivided into 4 classes, the classical and nonclassical cannabinoids, the aminoalkylindoles and the icosanoids [cf. Pharmacol. Rev. 1986, 38, 75; Eur. Med. Chem. 1996, 3, 101; Cannabinoid Receptors, R. Pertwee (Ed.), Academic Press, San Diego, 1995; J. Med. Chem. 1976, 19, 445; J. Med. Chem. 1976, 19, 454; J. Med. Chem. 1976, 19, 461, WO 95/33429; DE 2416491; J. Med. Chem. 1996, 36, 3875; U.S. Pat. No. 4,371,720; Curr. Med. Chem. 1996, 3, 101; Curr. Pharm. Design 1995, 1, 343; Tetrahedr. Lett. 1994, 50 2671; Life Sci. 1995, 56, 2007; Johnson, M. R., Melvin, L. S. in xe2x80x9cCannabinoids as Therapeutic Agents; Mechoulam R., Ed.; CRC Press, Boca Raton Fl 1986, pp. 121-145; J. Med. Chem. 1984, 7, 67; Pharmacol. Rev. 1986, 38, 1; Exp. Opin. Invest. Drugs 1996, 5, 1245; Pharmacol. Rev. 1986, 38, 151; Drug Design and Discovery 1995, 13, 155; J. Pharm. Exp. Ther. 1993, 265, 218; US 4391827; J. Med. Chem. 1995, 38, 3094; Bioorg. Med. Chem. Lett. 6, 1996, 17; J. Med. Chem. 1992, 35, 124; J. Med. Chem. 1991, 34, 1099; Bioorg. Med. Chem. Lett. 4, 1994, 563; Bioorg. Med. Chem. Lett. 5, 1995, 381; U.S. Pat. No. 5,112,820; Tetrahedr. Lett. 1995, 1401; J. Med. Chem. 1996, 39 4515; Drugs of Today 32, 1996, 275; J. Med. Chem. 1996, 39, 471; J. Med. Chem. 1994, 37, 1889; Mol. Pharmacol. 46, 516, 1994; Biochem. Pharmacol. 1995, 50, 83; J. Med. Chem. 1993, 36, 3032; Biochem. Pharmacol. 1994, 48, 1537; J. Biol. Chem. 1994, 269, 22937; Proc. Natl. Acad. Sci 1993, 90 7656; J. Prostagl. Leukotr. Essen. Fatty Acids 1995, 52, 83; Science 1992, 258 1946; Life Sci 1995, 56, 2041; FEBS Lett. 1994, 350, 240; Showalter V. M.; J. Pharmacol. Exp. Therap. 1996, 989; Pharm. Res. 13, 1996, 62; J. Med. Chem. 1997, 40, 659].
It is additionally known that cerebral apoplexy is a result of a sudden circulatory disorder of a human brain area with subsequent functional losses, with corresponding neurological and/or psychological symptoms. The causes of cerebral apoplexy can lie in cerebral haemorrhages (e.g. after a vascular tear in hypertension, arteriosclerosis and apoplectic aneurysms) and ischaemias (e.g. due to a blood pressure drop crisis or embolism). The functional losses in the brain lead to a degeneration or destruction of the brain cells (cf. Journal of Cerebral Blood Flow and Metabolism 1981, 1, 155; Chem. Eng. News 1996 (May 13), 41; Trends Pharmacol. Sci. 1996, 17, 227). Craniocerebral trauma is understood as meaning covered and open cranial injuries with involvement of the brain [cf. Schweiz. med. Wschr. 1993, 123, 449].
After a cerebral vascular occlusion, only a part of the tissue volume is destroyed as a direct result of the restricted circulation and the decreased oxygen supply associated therewith [cf. Neurology 1996, 47, 884]. This tissue area designated as the infarct core can only be kept from dying off by immediate recanalization of the vascular closure, e.g. by local thrombolysis, and is therefore only limitedly accessible to therapy. The outer peripheral zone, which is as least just as large in terms of volume, also designated as the penumbra, admittedly also discontinues its function immediately after onset of the vascular occlusion, but is initially still adequately supplied with oxygen by the collateral supply and irreversibly damaged only after a few hours or even only after days. Since the cell death in this area does not occur immediately, a therapeutic opportunity reveals itself to block the unfavourable development of the course of the disease both after stroke and after trauma.
The numerous therapeutic starting points for the reduction of the infarct volume include, for example, the blocking of glutamate receptors or glutamate release, free radical scavengers, anti-inflammatory substances, substances for blocking voltage- dependent calcium or sodium channels, and GABA agonists [cf. Trends Pharmacol. Sci. 17, 1996, 227].
The inhibition of glutamatergic neurotransmission or inhibition of glutamate release can be achieved by a multiplicity of substances having differing pharmacological actions and thus differing mechanisms of action [GABA receptor ligands (Neurosci. Lett 1990, 118, 99, Br. J. Pharmacol. 1997, 120, 60), aluminium (Neurotoxicol. 1992, 13, 413), ethanol (Eur. J. Pharmacol. 1992, 219, 469), barbiturates, for example thiopental (Br. J. Pharmacol. 1996, 119 1498), adenosine Al receptors (Neurosci. Lett. 1996, 220, 163), xcex12-agonists (Anesthesiol. 1996, X, 551), cannabinoid receptor agonists (J. Neurosci. 1996, 16, 4322).
For kynurenic acid (Brain Res. 1992, 592 333) and theophylline (Brain Res 1991, 565, 353), it has been shown that these substances, although they markedly inhibit glutamate release in vitro, have no neuroprotective action in vivo. In contrast to the speculation by Shen et al. (J. Neurosci. 1996, 16, 4322) the cannabinoid receptor agonist HU210, the (xe2x88x92)-enantiomer of HU-211, which is inactive on the cannabinoid receptor, is non-neuroprotective in a craniocerebral trauma model (J. Neurotrauma 1993, 10, 109).
It has now been found that the known cannabinoid CB1 receptor agonists cited above are surprisingly suitable for the prophylaxis and treatment of neurodegenerative disorders, in particular of cerebral apoplexy and craniocerebral trauma.
Preferably, [A] known agonists of the central cannabinoid receptor CB1 of the general formula (I) 
in which
A and D are identical or different and, depending on the position of a single or double bond, represent a C atom or the CH group,
E depending on the position of a single or double bond, represents the CH or CH2 group or a sulphur atom,
G, L and M are identical or different and, depending on the position of a single or double bond, represent a radical of the formula xe2x80x94CR5, xe2x80x94CR6R7 or Nxe2x80x94R8,
in which
R5, R6, R7 and R8 are identical or different and denote hydrogen, hydroxyl, formyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, or denote (C1-C6)-alkyl which is optionally substituted by hydroxyl or (C1-C4)-alkoxy,
or
R6 and R7 together represent a radical of the formula xe2x95x90O,
a represents a number 0 or 1,
R1 represents hydrogen or hydroxyl, or represents (C1-C11)-alkyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl or (C1-C4)-acyloxy, each of which is optionally substituted by hydroxyl, (C1-C10)-alkoxy or by a group of the formula xe2x80x94NR9R10,
in which
R9 and R10 are identical or different and denote hydrogen, phenyl, (C1-C4)-alkyl,
or
R9 and R10, together with the nitrogen atom, form a 5- to 7-membered saturated heterocycle which can optionally additionally contain a further heteroatom of the series S and O or a radical of the formula xe2x80x94NR11,
in which
R11 denotes hydrogen, phenyl, (C1-C6)-alkyl or (C1-C6)-acyl,
R2 represents (C1-C10)-alkyl or (C1-C10)-alkoxy, each of which is optionally substituted by phenyl, halogen, hydroxyl, azido, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, (C1-C4)-alkoxy or (C1-C4)-alkoxycarbonyl or by a group of the formula xe2x80x94NR12R13,
in which
R12 and R13 are identical or different and have the meanings of R9 and R10 indicated above,
R3 and R4 are identical or different and represent hydrogen or (C1-C6)-alkyl which is optionally substituted by hydroxyl,
or
R3 and R4 together represent a radical of the formula H2Cxe2x95x90,
T represents (C1-C6)-alkyl or (C2-C6)-alkenyl,
and
V represents hydroxyl,
or
T and V together with a ring closure represent an oxygen atom or a radical of the formula xe2x80x94NR14,
in which
R14 denotes hydrogen or methyl
with the exception of compounds of the following configuration 
[B] non-classical cannabinoids of the general formula (Ia) 
in which
R1xe2x80x2 and R2xe2x80x2 are identical or different and have the meanings of R1 and R2 indicated above,
R15 and R16 are identical or different and represent hydrogen or (C1-C8)-alkyl which is optionally substituted by hydroxyl,
or
R15 and R16, together with inclusion of the Cxe2x80x94C bond, form a phenyl ring or a 3- to 7-membered carbocyclic ring, where the ring systems are optionally substituted by (C1-C6)-alkoxycarbonyl or (C1-C8)-alkyl which for its part can be substituted by hydroxyl,
R17 represents hydrogen,
or
R16 and R17 together form a 6-membered saturated, partially saturated or unsaturated heterocycle which can contain a heteroatom of the series S and O or a radical of the formula xe2x80x94NR18,
in which
R18 denotes hydrogen or (C1-C4)-alkyl,
and where the ring systems are optionally substituted up to 3 times identically or differently, also geminally, by (C1-C8)-alkyl which for its part can be substituted by hydroxyl,
[C] the aminoalkyl indoles of the general formulae (Ib) and (Ic) 
in which
R19 and R191 are identical or different and represent (C6-C10)-aryl or a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms of the series S, N and/or O, each of which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of: nitro, halogen, trifluoromethyl, hydroxyl, carboxyl, or by (C1-C5)-acyl, (C1-C6)-alkoxy, (C1-C6)-alkylthio, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkyl which for its part can be substituted by hydroxyl,
R20 represents hydrogen or methyl,
R21 and R22 are identical or different and represent hydrogen or (C1-C6)-alkyl, or
R21 and R22, together with the nitrogen atom, form a 5 to 7-membered, saturated or partially saturated heterocycle which can optionally contain a further oxygen or sulphur atom or a radical of the formula xe2x80x94NR28,
in which
R28 has the meaning of R8 indicated above and is identical to or different from this,
R23 represents hydrogen, halogen, hydroxyl, (C1-C8)-alkyl or (C1-C8)-alkoxy,
R24 represents hydrogen or (C1-C6)-alkyl,
R25 represents hydrogen, phenyl, cycloalkyl having 3 to 8 carbon atoms, or (C1-C6)-alkyl which is optionally substituted by a group of the formula xe2x80x94NR29R30,
in which
R29 and R30 are identical or different and have the meaning of R9 and R10 indicated above,
R26 and R27 represent hydrogen, or together with inclusion of the double bond form a phenyl ring,
[D] compounds of the general formula (Id) 
in which
R31 has the meaning of R19 indicated above and is identical to or different from this,
R32 represents hydrogen, (C1-C3)-alkyl or (C1-C3)-alkoxy,
R33 and R34 have the meaning of R21 and R22 indicated above and are identical to or different from this,
and [E] eicosanoids of the general formula (Ie) 
in which
Y and Yxe2x80x2 represent hydrogen,
or
Y and Yxe2x80x2 together represent a radical of the formula xe2x95x90O or xe2x95x90S,
R35 represents (C16-C30)-alkenyl having at least three double bonds,
R36 represents trifluoromethyl or a group of the formula xe2x80x94OR37 or xe2x80x94NR38R39,
in which
R37 denotes hydrogen or (C1-C10)-alkyl which is optionally substituted by one or more, identical or different substituents which are selected from the group which consists of: hydroxyl, halogen, trifluoromethyl, (C6-C10)-aryl and (C1-C6)-alkoxy,
R38 and R39 have the meaning of R37 indicated above and are identical to or different from this,
or
R38 and R39, together with the nitrogen atom, form a 5- to 7-membered saturated heterocycle which can optionally contain a further heteroatom of the series S and O or a group of the formula xe2x80x94NR40,
in which
R40 has the meaning of R8 indicated above and is identical to or different from this,
and their salts and isomeric forms,
are used in the control of neurodegenerative disorders, in particular cerebral apoplexy and craniocerebral trauma.
The compounds used according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Very particularly preferred salts are those mentioned above which are formed by the amine function.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
In the context of the present invention, the substituents in general have the following meaning:
(C1-C11)-, (C1-C10)-, (C1-C8)-, (C1-C6)-, (C1-C4)- and (C1-C3)-alkyl in general represent, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 1 to 11 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.
(C16-C30)- and (C2-C6)-alkenyl in general represent, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical having 2 to 30 carbon atoms and one or more, preferably having one, two or at least 3 double bonds. Examples which may be mentioned are allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.
(C2-C6)-Alkinyl in general represents a straight-chain or branched hydrocarbon radical having 2 to 6 carbon atoms and one or more, preferably having one or two triple bonds. The lower alkyl radical having 2 to approximately 5 carbon atoms and a triple bond is preferred. An alkenyl radical having 2 to 4 carbon atoms and a triple bond is particularly preferred. Examples which may be mentioned are acetylene, 2-butine, 2-pentine and 2-hexine.
Cycloalkyl in general represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. The cyclopropane, cyclopentane and the cyclohexane rings are preferred.
Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Aryl in general represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
(C1-C10)-, (C1-C6)- and (C1-C4)-alkoxy in general represent, depending on the abovementioned substituents, a straight-chain or branched hydrocarbon radical bonded via an oxygen atom and having 1 to 10 carbon atoms. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy octoxy or isooctoxy.
(C1-C6)- and (C1-C5)-acyl in general represent straight-chain or branched lower alkyl having 1 to 6 carbon atoms which are bonded via a carbonyl group. Examples which may be mentioned are: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
(C1-C6)- and (C1-C4)-alkoxycarbonyl can be represented, for example, by the formula 
Alkyl in this connection represents a straight-chain or branched hydrocarbon radical having 1 to 6 or 1 to 4 carbon atoms. Examples which may be mentioned are the following alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
(C1-C6)-Alkylthio in general represents a straight-chain or branched hydrocarbon radical bonded via a sulphur atom and having 1 to 6 carbon atoms. Examples which may be mentioned are methylthio, ethylthio and propylthio.
(C1-C4)--Acyloxy can be represented, for example, by the formula 
Alkyl in this connection represents a straight-chain or branched hydrocarbon radical having 1 to 4 carbon atoms. Examples which may be mentioned are the following acyloxy radicals: methcarbonyloxy, ethylcarbonyloxy and propylcarbonyloxy.
Saturated, partially saturated and unsaturated heterocycle in the context of the present invention in general represents a 5- to 7-membered, preferably 5- to 6-membered, heterocycle which can contain up to 3 heteroatoms of the series S, N and/or O. Examples which may be mentioned are: pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, pyrimidyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated in a known manner into the stereoisomerically uniform constituents.
Preferably used compounds according to the invention are those of the general formula (I),
in which in the compounds of the general formula (I)
A, D, E, G, a, L, M, T and V have the meaning indicated above,
R1 represents hydroxyl or the radical of the formula xe2x80x94Oxe2x80x94COxe2x80x94CH3 or xe2x80x94Oxe2x80x94COxe2x80x94(CH3)xe2x80x94N(C2H5)2,
R3 and R4 together represent the xe2x95x90CH2 radical,
or
R3 and R4 represent hydrogen, methyl or the (CH2)3xe2x80x94OH radical,
in which in the compounds of the general formula (Ia),
R2xe2x80x2 and R17 have the meaning indicated above,
R1xe2x80x2 represents hydroxyl,
R15 and R16 represent hydrogen, or together with the inclusion of the Cxe2x80x94C bond form a pyridyl or CHxe2x80x94OHxe2x80x94 substituted phenyl ring,
in which in the compounds of the general formula (Ib)
R19 represents naphthyl,
R20 represents methyl,
R23 represents hydrogen,
and
R21 and R22, together with the nitrogen atom, form a morpholine ring, in which in the compounds of the general formula (Ic)
R19xe2x80x2 represents methoxy-substituted naphthyl,
R24 represents hydrogen,
R25 represents phenyl, (C1-C6)-alkyl or the radical 
R26 and R27 represent hydrogen or phenyl,
in which in the compounds of the general formula (Id)
R31 represents napthyl which is optionally substituted by methoxy,
R32 represents hydrogen or methyl,
R33 and R34, together with the nitrogen atom, represents morpholine,
in which in the compounds of the general formula (Ie)
Y and Yxe2x80x2 represent hydrogen or together represent the xe2x95x90O radical,
R35 represents (C16-C21)-alkenyl,
and
R36 represents trifluoromethyl or the radical of the formula xe2x80x94NR38R39,
in which
R38 and R39 are identical or different and denote hydrogen or (C1-C3)-alkyl which is optionally substituted by fluorine or hydroxyl,
and their salts and isomeric forms,
in the control of neurodegenerative disorders, in particular cerebral apoplexy and craniocerebral trauma.
The following compounds: 
are very particularly preferably used for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy and craniocerebral trauma.
The abovementioned known compounds can be prepared by customary methods [cf. the abovementioned references].
Cannabinoid receptor CB-1 agonists in the sense of the invention are compounds which in the CB-1 luciferase reporter gene test described below have an IC50 value of less than 10xe2x88x925 M.